High rates of chronic upper and lower airways disease have occurred in Fire Department of the City of New York (FDNY) workers exposed to the World Trade Center (WTC) disaster site between 9/11/2001 and 9/24/2001. The effect of WTC exposure on lung function was greater in some individuals than others. We initiated a biomarker discovery program using 8,000 serum collected within 6 months of WTC exposure to identify who was at greatest risk for adverse outcomes. To enhance our biomarker discovery program, 2,132 WTC-exposed rescue and recovery workers had serum collected between 12/2013 and 10/2015. We have identified multiple cytokines that predict future abnormal FEV1 using serum that was drawn and stored between 10/2001 and 3/2002. Since a majority of firefighters with respiratory symptoms and reactive airway disease have normal FEV1, we explored the rate of decline in FEV1 as another definition of a poor outcome. In a longitudinal study of WTC-exposed firefighters, we recently observed that about 20% had > 64 ml/year decline in FEV1, which was more than twice the average age-related decline of 32 ml/year (henceforth enhanced- FEV1-decline). Examination of the complete blood count (CBC) data stored in the WTC Medical Monitoring and Treatment Program data warehouse has revealed that higher eosinophil (Eos) and polymorphoneutrophil (PMN) concentrations are risk factors for enhanced-FEV1-decline post-9/11. Examination of available serum biomarker data from two distinct subsets of this population revealed that IgE is also a risk factor for enhanced- FEV1-decline. This proposal will confirm and extend these preliminary observations with biomarker studies on larger, more representative subsets of WTC-exposed rescue and recovery workers. We propose to use the recently obtained serum to test if biomarkers such as IgE are persistently elevated in the enhanced-FEV1- decline group. Specific AIM 1 will test the hypothesis that Eos, PMN, IgE and inflammatory cytokines measured in the 6 months post-9/11 are risk factors for enhanced-FEV1-decline using a case-control design with frequency matching. Specific AIM 2 will test the hypothesis that the IgE and cytokines measured in the 6 months post-9/11 will be associated incident airway reactivity.Specific AIM 3 will test the hypothesis that persons with high levels IgE and cytokines measured in the 6 months post-9/11 will continue to show high levels in 2013-2015. If elevated biomarker levels persist, then the information derived from this research might be applied to those without stored serum. The primary goal of this investigation is to validate biomarkers of progressive decline in lung function and airway reactivity. The ultimate goal of this line of investigation is to develop risk stratification models to identify subpopulations at high risk of adverse pulmonary outcomes after intense irritant exposure. This will allow for more intensive monitoring and early treatment of high risk individuals, instead of devoting costly resources toward intensive screening of low risk individuals.